Iodo carboxymethyl dextran and methods of making it



United States Uatent IODO CARBOXYMETHYL DEXTRAN AND METHODS MAKING ITLeo J. Novak, Dayton, Ohio, assignor to The Commonwealth EngineeringCompany of Ohio, Dayton, Ohio, a corporation of Ohio No Drawing.Application September 21, 1955, Serial No. 535,728

12 Claims. (Cl. 260-209) This invention relates to carboxymethyl iodinecompounds or absorption complexes and to methods of producing them.

As is well known, iodine has certain undesirable properties. It oftenexhibits an irritating effect on the skin and delicate tissues, and istoxic if taken internally. These properties have limited both theinternal and external use of iodine in its free and combined form, sincethe use of iodine in a quantity sufficient for it to exert its curativeproperties frequently results in serious damage to the skin or to bodyorgans.

Various attempts have been made to prevent or inhibit the development ofserious damage resulting from the caustic, irritating and toxic efiectsof iodine. Thus, it has been proposed to use iodine in the form ofmixtures thereof with organic and inorganic adjuvants or of compounds ofiodine with organic and inorganic bases. However, for the most part, theknown chemical compounds and physical mixtures have the drawback of alsobeing toxic or of comprising the iodine only in small or ineffectiveamounts. There has been, also, the problem of controlling thecomposition of the chemical compounds in those instances involvingchemical reaction of the iodine with another substance.

One object of this invention is to provide new chemical compoundscontaining iodine which are non-irritating and the M. L. D. and L. D.50of which can be controlled.

Another object is to provide a series of new chemical entities ofvarying, controllable iodine content.

A further object is to provide water-soluble iodine containingcompounds.

These and other objects are accomplished by the present invention whichprovides carboxymethyl dextran-iodine compounds obtained by combiningiodine with carboxymethyl dextran containing some free hydroxyl groups,whereby hydroxyl groups on the anhydroglucose units of the dextran arereplaced by iodine.

The carboxymethyl dextran may be obtained as described in the pendingapplication of L. I. Novak et 211., Serial No. 346,016, filed March 31,1953. According to that method, the selected dextran and acarboxymethylating agent are reacted together in water containing strongalkali metal hydroxide, the carboxymethyl group being substituted forone or more hydroxyl groups of the dextran molecule.

Suitable carboxymethylating agents are chloracetic acid, sodiumchloracetate and chloracetamide.

Suitable hydroxides are sodium, potassium and lithium hydroxide.

In a preferred embodiment, an aqueous solution or suspension of thedextran containing an excess of sodium or potassium hydroxide and anexcess of sodium or potassium chloracetate is heated at 50-100 C. forten minutes to two hours. The molar ratio of sodium or potassiumchloracetate to dextran may be between 2:1 and 12:1, the molar ratio ofsodium or potassium hydroxide to dextran may be between :1 and 15:1, themolar ratio of water to dextran between 70:1 and 120:1.

7 2 The proportions and heating time are selected and correlated toyield a carboxymethyl dextran containing an average of 0.5 up to but notmore than 2.0 carboxymethyl groups per anhydroglucose unit of thedextran.

The reaction product is a viscous mass comprising the alkali metal saltof the dextran ether. The salt is precipitated from the crude product bymeans of a water-miscible aliphatic alcohol or ketone.

The free ether is recovered from the salt by dissolving the latter inwater, acidifying to pH 2.0-3.0, and adding a water-miscible aliphaticalcohol or acetone to precipitate the ether.

The dextran converted to the carboxymethyl ether may be native, highmolecular weight microbiologically produced dextran as biosynthesizedfrom sucrose by the action of microorganisms of the Leuconostocmesenteroides or L. dextranicum types or by their enzymes. Or it may bea partial hydrolyzate of the native dextran. In general, the dextran mayhave a molecular weight between 2000. and that of the native material.The presently preferred dextran is native, unhydrolyzed watersolubledextran.

The following illustrates the production of a carboxymethyl dextransuitable forcombination with iodine to produce the new compounds of theinvention.

One hundred parts of particulate purified native (unhydrolyzed)water-soluble dextran were dissolved in 700 parts of water. One hundredand fifty parts of sodium hydroxide were dissolved in 150 parts ofwater, and the dextran and sodium hydroxide solutions were mixedtogetherwith agitation. Two hundred and twenty parts of monochloracetic acidwere dissolved in 400 parts of water and 112.3 parts of anhydrous sodiumcarbonate were added to the solution. The resulting sodium chloracetatesolution was then slowly added to the mixed dextran and sodium hydroxidesolutions, and the masswas heated for one hour at 65 C. The reactionmass was then adjusted to pH of 3.0 with hydrochloric acid and pouredslowly into 1500 parts of methanol. The precipitate was substantiallyfreed of methanol and water by passage through squeeze rolls, then driedunder vacuum and reduced-to particulate condition (SO-mesh) in a hammermill. The ether thus obtainedcontained by analysis, an average of about1.0 carboxymethyl group per anhydroglucose unit of the dextran.

The carboxymethyl dextran-iodine compounds may be prepared by dissolvingthe carboxymethyl dextran in water, adding powdered crystalline U. S. P.iodine or Lugols solution to the dextran solutionwith stirring, holdingthe mixture, stirring being continued, until the iodine combines withthe dextran ether to form a compound which is iodo-carboxymethyl dextranin solution. The solution may be used as such, after dilution withWater, or the compound may be recovered by evaporation of the water,preferably by low temperature vacuum evaporation or by lyophilization.

The mass comprises the carboxymethyl dextran solution containing theiodine, or Lugols solution and may be heated to 6065 C. to expediteformation of the compound, if desired.

According to another embodiment, the carboxymethyl dextran is dispersedin an organic solvent which is a chlorine acceptor, such as pyridine,and which contains a sulfonic acid chloride. The latter reacts with thecarboxymethyl dextran to produce the sulfonyl chloride thereof. Thepyridine or the like is removed by distillation, the residue isdissolved in alcohol, the solution is neutralized, an alkali metaliodide such as sodium or potassium iodide is added, and the mass isheated at 12 0 C. for three. to five hours or until the desiredcarboxymethyl dextran iodide is formed; The crude 3 reaction product isworked up to recover the iodine-substituted ether.

Carboxymethyl dextran-iodine compounds of predetermined and controllediodine content are obtained. A wide range of such compounds may beproduced, adapted for specific purposes or uses depending on the D. S.of the starting carboxymethyl dextranwith respect to carboxymethylgroups, the molecular weight of the dextran from which the ether isderived, and the average number of hydroxylgroups replaced by iodine.

The iodo-carboxymethyl dextran compound may contain 0.5 to 2.0carboxymethyl groups-and have an average of 1.0 to 2 .5 hydroxylsreplaced by iodine, per AGU. The ratio of carboxymethyl dextran toiodine oriodide used may be'from 1:3 to 1:15.

The compounds may be used for any of the usual purposes to which iodineis adaptedgand the compound selected may have a higher or lower iodinecontent as indicated for a particular curative or disinfectant effect.Aqueous solutions of the iodine-substituted carboxymethyl dextran may beused as X-ray contrast media which cause structures of the kidney tobecome visible under X-ray observation. The carboxymethyl dextranportion of the product is a carrier for and control of the release ofthe iodine to the site of application.

The following examples are illustrative of specific embodiments of theinvention, it being understood that these examples are not limitative.

Example I About 300 grams of carboxymethyl dextran (derived from native,unhydrolyzed water-soluble dextran and containing an average of about1.0 carboxymethyl group per anhydroglucose unit) are dispersed in 2500cc. of pyridine. The dispersion is cooled to -5 C. About 325 grams ofp-toluene sulfonyl chloride are added in small increments over a periodof about a half hour, and with continued stirring. The solution is letstand for about a half hour, after which the major portion of the freepyridine is distilled off under vacuum. The residue is dissolved in 500cc. of alcohol, 500 cc. of water are added, and the solution isneutralized with a sodium hydroxide solution using bromthymol blue asindicator. The solvent is taken off under vacuum, the residue is mixedwith' six liters of acetone, refrigerated for about 12 hours and thenfiltered to remove the insolubles. The acetone solution is concentratedto about 1.2 liters and 200 grams of sodium iodide are dissolved in it,the

solution being then heated to about 100 C. for about 7 four hours. Afterit is cooled, the reaction mass is filtered, the solvent taken off thefiltrate under vacuum, and the residue dissolved in 700 cc. of water.The aqueous solution is extracted twice with methylene dichloride,brought to neutrality with aqueous sodium hydroxide and the water isdistilled off under vacuum. The resulting water-solublemono-iodo-carboxymethyl dextran is purified by dissolving it in waterand reprecipitating it by means of alcohol.

Instead of using p-toluene sulfonyl chloride and forming theiodo-dextran ether through the intermediate sulfonyl chloride of theether, the acid chlorides of other sulfonic acids may be used, such asthe chlorides of ethane-sulfonic, methane-sulfonic, and benzenesulfonicacids. Instead of pyridine, other inert organic solvent chlorineacceptors may be used for dispersing the carboxymethyl dextran.

Example 11 About parts of carboxymethyl dextran (derived from nativeunhydrolyzed water-soluble dextran and containing anaverage of about 0.5carboxymethyl groups per AGU) are dissolved in 500 parts of distilledwater.

About 10 parts of Lugols solution (5% iodine, 10% potassium iodide) areadded with stirring. The mass is heated at C. for 2 hours, stirringbeing continued.

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The resulting clear solution contains carboxymethyl dextran iodide inwhich an average of abouttwo of the initially free hydroxyl groups perAGU of the dextran ether are replaced by iodine. The iodo-dextran ethercan be recovered by precipitation from solution with methanol andpurified by dissolution thereof in water and re-precipitation usingmethanol as the precipitant.

Example III Example I is repeated, using carboxymethyl dextran derived.from clinical dextran and containing an average of about 1.0carboxymethyl group per AGU.

Example IV Example II is repeated using 300 gms. of particulatewater-soluble carboxymethyl dextran derived from native unhydrolyzedinitially water-insoluble dextran and containing an average of 2.0carboxymethyl groups per AGU.

Example V 800 cos. of water are added, and the solution is neutralizedwith 20% sodium hydroxide solution. The solvent is taken off undervacuum, the residue mixed with 10 liters of acetone, refrigerated forabout 12 hours and filtered to remove insolubles. The acetone solutionis concentrated to about 3 liters and 400 grams of potassium iodide aredissolved in it. The solution is heated to about C. for five hours.After cooling, the reaction mass is filtered, the solvent taken off thefiltrate under vacuum, and the residue is dissolved in it. The solutionis heated to about 100 C. for five hours. After cooling, the reactionmass is filtered, the solvent taken off the filtrate under vacuum, andthe residue is dissolved in 1000 cc. of Water. The aqueous solution isextracted twice with methylene dichloride, brought to neutral withaqueous sodium hydroxide, and the Water is distilled off under vacuum.Water-soluble di-iodo-carboxymethyl dextran is obtained and purified tore-precipitation from aqueous solution, using alcohol as theprecipitant.

Example VI Example II is repeated using 300 grams of carboxymethyldextran derived from hydrolyzed dextran of molecular weight about 2000and containing an average of about 1.0 carboxymethyl group per AGU.

Example VII Example II is repeated using 300 grams of the carboxymethylether of hydrolyzed dextran of molecular weight about 500,000 andcontaining an average of about 1.0 carboxymethyl group per AGU.

Since variations and changes may be made in carrying out the inventionwithout departing from its spirit and scope it is to be understood thatthe invention is not in tended to be limited except as defined in theappended claims.

What is claimed is:

1. As a new compound, iodo-carboxymcthyl dextran containing peranhydroglucose-unit an average of 0.5 to 2.0 carboxymethyl groups and inwhich an average of 1.0 to 2.5 of the hydroxyl groups initially presentin the carboxymethyl dextran per anhydroglucose unit are replaced byiodine.

2. As a new compound, mono-iodo-carboxymethyl dextran.

3. As a new compound, di-iotlo-carboxymethyl dextran.

4. The method of making iodo-carboxymethyl dextran which comprisesdissolving carboxyrnethyl dextran containing, per anhydroglucose unit,an average of 0.5 to 2.0 carboxymethyl groups, in water, adding iodineto the solution, and heating the solution with stirring until theiodocarboxymethyl dextran is formed.

5. The method according to claim 4, characterized in that the iodine isadded to the carboxymethyl dextran solution in the form of a solutionthereof in potassium iodide.

6. The method according to claim 4, characterized in that thecarboxymethyl dextran is derived from native, unhydrolyzed dextran.

7. The method according to claim 4, characterized in hat thecarboxymethyl dextran is derived from clinical extran.

8. The method of making iodo-carboxymethyl dextran which comprisesdispersing carboxymethyl dextran containing per anhydroglucose unit anaverage of 0.5 to 2.0 carboxymethyl groups in a solution of a sulfonicacid chloride in an organic solvent that is a chlorine acceptor,removing a major portion of the solvent, dissolving the residue inalcohol, diluting the solution with water, removing the alcohol undervacuum, adding acetone to the residue, adding an alkali metal iodide tothe acetone solution, heating the solution to 120 C. for three to fivehours, and recovering the iodo-carboxymethyl dextran therefrom.

9. The method according to claim 8, characterized in that the organicsolvent chlorine acceptor is pyridine.

10. The method according to claim 8, characterized in that the sulfonicacid chloride is p-toluenesulfonic acid chloride.

11. The method according to claim 8, characterized in that thecarboxymethyl dextran is derived from native, unhydrolyzed water-solubledextran.

12. The method according to claim 8, characterized in that thecarboxymethyl dextran is derived from clinical dextran.

References Cited in the file of this patent UNITED STATES PATENTS2,365,776 Raymond et a1. Dec. 26, 1944 2,448,510 Barham Sept. 7, 19482,562,882 Barham Aug. 7, 1951 2,677,645 Allen May 4, 1954

1. AS A NEW COMPOUND, IODO-CARBOXYMETHYL DEXTRAN CONTAINING PERANHYDROGLUCOSE UNIT AN AVERAGE OF 0.5 TO 2.0 CARBOXYMETHYL GROUPS AND INWHICH AN AVERAGE OF 1.0 TO 2.5 OF THE HYDROXYL GROUPS INITIALLY PRESENTIN THE CARBOXYMETHYL DEXTRAN PER ANHYDROGLUCOSE UNIT ARE REPLACED BYIODINE
 4. THE METHOD OF MAKING IODO-CARBOXYMETHYL DEXTRAN WHICHCOMPRISES DISSOLVING CARBOXYMETHYL DEXTRAN CONTAINING, PERANHYDROGLUCOSE UNIT, AN AVERAGE OF 0.5 TO 2.0 CARBOXYMETHYL GROUPS, INWATER, ADDING IODINE TO THE SOLUTION, AND HEATING THE SOLUTION WITHSTIRRING UNTIL THE IODOCARBOXYMETHYL DEXTRAN IS FORMED.